Project Summary Candida albicans is a commensal species that occupies diverse niches of the human body. It is also a prevalent opportunistic pathogen, being a frequent cause of debilitating mucosal infections and life-threatening systemic infections. In many cases, the commensal form is responsible for seeding systemic disease, which is often precipitated by a breakdown in host immunity. Despite its clinical importance, there remains limited understanding of commensal interactions between C. albicans and the host, or the fungal traits that influence invasion and disease during a disseminated infection. One of the most notable attributes of C. albicans is its ability to grow in different heritable states and morphological forms. The ability to transition between different phenotypic states can enable adaptation to host niches and modulate interactions with the immune system. Epigenetic mechanisms have been shown to regulate heritable switching between cell states, yet it is not known why only some clinical isolates undergo certain phenotypic switches, or how transitions between cell states determines outcomes in interactions with the host. We now propose a genetic mechanism underlies an important cell state transition in C. albicans that impacts both commensal and pathogenic behavior. C. albicans is a heterozygous diploid species and we made the unexpected observation that many clinical isolates are poised to undergo differentiation due to being functionally heterozygous for a key transcription factor. Furthermore, such heterozygous strains frequently lose the functional copy of the transcription factor gene both during laboratory culture and during infection of the host. The direct consequence of this transformative event is generation of a cell state that is hypercompetitive both in commensal and disseminated infection models. The goals of the current project are (1) to establish that changes in a master transcription factor gene direct a clinically relevant phenotypic switch, (2) to define whether the transcription factor gene represents a genomic hotspot for mutagenesis and/or recombination events, and (3) to examine cell state transition events during infection of the mammalian host, as well as the properties of different cell states that define fungal behavior in commensal and pathogenic models of infection. The proposed studies will provide new insights into how C. albicans adapts to different niches in the host, including an unexpected mechanism by which genetic polymorphisms and genomic plasticity combine to drive cell differentiation. These experiments will establish an important paradigm for C. albicans biology, as it is likely that other heterozygous loci are similarly primed for genetic events that drive adaptation in the host.